alpha2 adrenergic receptors are found throughout the body and play a critical role in regulating multiple organ systems. At least three separate alpha2 adrenoceptor subtypes are known to exist (alpha2a, alpha2b, and alpha2c) although little is known about each subtype's specific function. Functional studies are difficult because highly selective agonists are not available. We intend to characterize the alpha2a adrenoceptor's function by developing mice that lack the alpha2a adrenoceptor. Gene targeting vectors will be constructed to inactivate the alpha2a adrenoceptor gene and used for homologous recombination in embryonic stem cells (ES cells). Transfected ES cells are reintroduced into a host embryo and the progeny are screened for germline contribution. Animals with germline contribution can then transmit the mutation and produce non-chimeric offspring heterozygous for the mutation. Heterozygotes are bred to produce animals homozygous for the inactivated gene. The cardiovascular and neural physiology of the alpha2a knockout mice will be studied and compared with wild type, alpha2b and alpha2c knockout mice which have already been developed in our lab.